Usefulness of novobiocin as a selective inhibitor of intestinal breast cancer resistance protein (Bcrp) in rats

Abstract

1. We investigated whether novobiocin is useful for elucidating the contribution of breast cancer resistance protein (Bcrp) to intestinal absorption without affecting the activities of P-glycoprotein (P-gp), cytochrome P450 (CYP) 3 A and hepatic organic anion transporting polypeptide (Oatp) in rats.

2. To determine the effects of novobiocin on Bcrp, P-gp, CYP3A and Oatp activities, we used sulfasalazine, fexofenadine, bosentan and midazolam, respectively, as probe substrates. Each substrate was orally or intravenously administered to rats 15 min after oral novobiocin administration at a dose of 3 mg/kg.

3. Pre-treatment with novobiocin significantly increased the area under the plasma concentration–time curve and the peak plasma concentration of sulfasalazine after oral administration by 3.2- and 5.9-fold, respectively, in rats, whereas its systemic clearance following intravenous dosing was not influenced. These results indicate that novobiocin selectively inhibits intestinal Bcrp-mediated efflux with limited effects on extra-intestinal Bcrp activity.

4. In addition, novobiocin pre-treatment did not significantly alter the pharmacokinetic parameters of orally administered fexofenadine and midazolam or intravenously administered bosentan, suggesting that the effects of novobiocin on other processes were negligible.

5. These findings demonstrate that novobiocin permits estimating the net contribution of Bcrp to intestinal absorption of drug candidates.

Keywords:

• novobiocin
• Bcrp
• P-gp
• CYP3A
• Oatp
• rats
• intestine

Acknowledgements

The authors thank Takashi Sato (TOA EIYO LTD.) for valuable discussions. The authors also would like to thank Enago (www.enago.jp) for the English language review.

Disclosure statement

The authors report no declarations of interest.